SLC25A51 Decouples the Mitochondrial NAD+/NADH Ratio to control proliferation of AML cells
Introduction
The Cambronne Lab develops real-time genetically-encoded, single-fluorescent protein biosensors to elucidate the complex subcellular and temporal compartmentalization of metabolic pathways. Observations of mitochondrial NAD+ concentrations using the sensor led to our co-identification of inner mitochondrial membrane solute carrier SLC25A51 as the required transporter in human cells for sustaining cell respiration through its selective import of oxidized NAD+.
Methods
We observed an elevated expression of SLC25A51 that correlated with poorer outcomes in Acute Myeloid Leukemia (AML) patient data, and we sought to determine the role SLC25A51 may serve in this oxidative cancer.
Results
We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models; this was rescued by importing NAD+ or re-oxidization of mitochondrial NADH. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and forced glutamine utilization for reductive carboxylation to support aspartate production, notably without increased glycolytic flux. Consequently, partial depletion of SLC25A51 sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for supporting oxidative reactions from a variety of fuels and for a proliferative advantage.
Conclusion
SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.